The compound D-isoglutamyl-D-tryptophan (also known as H-D-γ-Glu-D-Trp-OH or H-D-iGlu-D-Trp-OH or iDD or D-(iEW) or timodepressin or thymodepressin) is a synthetic hemoregulatory dipeptide having the following chemical structure:

Thymodepressin is the free diacid and has the Chemical Abstracts Service (CAS) Registry Number® 186087-26-3. It is an immunosuppressant and selectively inhibits proliferation of bone marrow cells. It is effective in the suppression of the immune system during the transplantation of the bone marrow, organs and tissues (Semina, O. V et al. (2001) Bulletin of Experimental Biology and Medicine, 131(5), 493-495); the protection of the bone marrow cells and the immune system against the damaging effects of chemotherapy and radiation (U.S. Pat. Nos. 5,736,519, 6,103,699 and 6,410,515); and the treatment of autoimmune diseases, such as psoriasis and atopic dermatitis (Sapuntsova, S. G., et al. (May 2002), Bulletin of Experimental Biology and Medicine, 133(5), 488-490).
A method for the preparation of thymodepressin was disclosed in example 1 of U.S. Pat. Nos. 5,736,519, 6,103,699 and 6,410,515. However, the manufacture of thymodepressin on a large scale cannot be conducted using the experimental details of this method since a mixture of D-glutamyl-D-tryptophan and D-isoglutamyl-D-tryptophan is produced which must be separated and purified by ion exchange chromatography resulting in a very low yield (12.25%) of thymodepressin.
U.S. Pat. Nos. 5,736,519, 6,103,699 and 6,410,515 teach that the peptides disclosed therein may be converted into acid addition salts by reacting with inorganic acids including hydrochloric acid, sulphuric acid, hydrobromic acid, phosphoric acid, etc., or organic acids including formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid, benzenesulphonic acid, and toluenesulphonic acids. However, neither the base addition salts of thymodepressin nor methods for the preparation of such salts are disclosed in these patents.
Thymodepressin is not bioavailable as an oral drug in traditional tablet or capsule form. It is currently being sold in Russia as the di-sodium salt in liquid formulation for injection and intranasal administration for the treatment of psoriasis, atopic dermatitis and rheumatoid arthritis. The solid form of the di-sodium salt of D-isoglutamyl-D-tryptophan is an amorphous powder which is hygroscopic and very difficult to handle. The di-sodium salt of D-isoglutamyl-D-tryptophan has the molecular formula C16H17N3Na2O5 and the following chemical structure:

The di-sodium salt of D-isoglutamyl-D-tryptophan is not identified by the CAS Registry System, is not listed in the CAS REGISTRYSM File and does not have a CAS Registry Number® associated with it. The identification and structural confirmation of the di-sodium salt of D-isoglutamyl-D-tryptophan has been determined by infrared (IR) spectroscopy (Kashirin, D. M., et al. (2000), Pharmaceutical Chemistry Journal, 34(11), 619-622). However, although the di-sodium salt of D-isoglutamyl-D-tryptophan is known, its preparation, isolation and further characterization has not been disclosed.
Through investigations in our laboratory, we have determined that the freeze-dried di-sodium salt of D-isoglutamyl-D-tryptophan is extremely hygroscopic; turning into a gel in a matter of minutes in air, and thus cannot easily be handled. A powdery or amorphous form of a compound, intended for pharmaceutical use may give rise to manufacturing problems due to bulk density issues, hygroscopicity and variable water content that cannot be corrected by vacuum drying. D-isoglutamyl-D-tryptophan is a dipeptide and the drying of an amorphous form at elevated temperature, for example, 80-100° C. under vacuum is not recommended. Thus, there are serious difficulties experienced during the purification of the di-sodium salt of D-isoglutamyl-D-tryptophan and obtaining the pure di-sodium salt on a manufacturing scale. Further, as discussed above, there is no published procedure for its preparation.
The mono-sodium salt of D-isoglutamyl-D-tryptophan is identified by the CAS Registry System and is listed in the CAS REGISTRYSM File with a CAS Registry Number® of 863988-88-9 and has the following chemical structure:

However, there are no references citing the mono-sodium salt of D-isoglutamyl-D-tryptophan and thus no publication of its identity, its physical and/or chemical properties, its characterization in the solid state or a procedure for its preparation and isolation. Therefore, there is no supporting evidence for the existence of the mono-sodium salt of D-isoglutamyl-D-tryptophan.
Freeze-dried powders of mono-sodium and di-sodium salts of peptide drugs may not have controllable powder bulk density ranges for formulation and may require significant investment in freeze-dried dispersion technology.
Therefore, there is a need to develop pharmaceutically acceptable salts of D-isoglutamyl-D-tryptophan which are crystalline. Such crystalline salts can generally be purified more easily than an amorphous form and may possess other advantageous properties, for example in relation to their particular crystalline form and/or their solubility characteristics and/or their lack of hygroscopicity and/or their stability characteristics, including their thermal stability properties and/or their ability to undergo oxidative degradation.